The present invention relates generally to the field of bioelectromagnetics and more specifically to those systems designed to expose biological systems to biologically active electromagnetic fields in order to achieve beneficial clinical effects.
Time-varying magnetic fields are known to modify the behavior of cells and tissues. Biological activity due to a magnetic field is a function of both field amplitude and frequency.
When the amplitude of magnetic field changes, an electric field is induced in a conductive body such as a biological system. This electric field is an energy input into the system. Heretofore, it has widely been held that the resultant biological activity resides solely in the specifications of the resultant electric field. Toward devising systems that exploit the positive effects of induced electric fields in biological systems a number of solutions have been offered. Among these are R. Ryaby, et al. (U.S. Pat. No. 4,105,017), E. Findl (U.S. Pat. No. 4,428,366) and J. Delgado (U.S. Pat. No. 4,641,633). However, each of these patents stresses the primary of the induced electric field and disregards the biological activity of the magnetic field itself. It will be demonstrated in what follows that the electrical component need not be rigorously specified and that both the magnetic component of a time-varying field and an independent static magnetic field can and do contribute to the biological activity of a time-varying magnetic field in such a way that allows for the invention of a new and useful quasistatic biological cell and tissue modifier. Generally one embodiment of the invention is directed to a static magnetic field which modulates the effects of a time varying magnetic field to provide the ability to input more biologically meaningful energy into a system. Alternatively, it will be shown that a single time varying magnetic field may be used to accomplish similar results.
The inventor has observed that placing in-vitro nerve cultures or animals within Helmholtz coils and passing current through the coils to produce a magnetic pulse with a duration of 20 milliseconds, a flux density of between 0.4-3.0 gauss and a repetition rate of 2 Hertz has produced a number of enhanced regeneration responses. For instance, neuritic outgrowth of chick dorsal root ganglia cells in-vitro is enhanced by 35%; scar formation in transected and/or repaired sciatic nerves in rats and cats is reduced; the proportions of important biological molecules in regenerating sciatic nerves of rats is markedly shifted; the rate of axonal sprouting in a rat model where the sciatic nerve is crushed increased by 22%; and the ability of rats to recover from a transected sciatic nerve injury is enhanced by 15-20% as measured by performance in gait after short term post-operative treatment. The amount of scarring in a wound site of a rat is reduced; and the survival of tissue in a rat skin flap model is promoted by 33% due to increased blood circulation.
Preferably the flux density of the pulse is maintained at a constant intensity for approximately 20 milliseconds. The essential nature of the magnetic field dosage per se, can be demonstrated by shortening the pulse to 5 milliseconds. Whereas a pulse of 20 milliseconds at 0.4 gauss repeating at 2 Hertz enhances the growth of chick dorsal root ganglia in culture, a pulse of 5 milliseconds, but other identical, has no biological activity in this system whatsoever. Note that the duration of the pulse only affects the ambient magnetic field, not the induced voltage since this voltage is determined only by the rate of change of the pulse rise and fall.
In addition, if the rate of change of the pulse rise and fall were each reduced by two-fold or more while maintaining the pulse width at 20 milliseconds, there would be no change in the biological activity of the signal: 35% growth enhancement effect would be observed. This is an indication of the nonspecific nature of the induced electric field.
Furthermore, imposing a static magnetic field of 0.6 gauss in the same direction as the pulse field produces an even greater regeneration response in the in-vitro nerve culture system. Under these conditions growth enhancement of 60% was observed. However, the static magnetic field by itself did not produce an effect. This observation demonstrates that the time-varying field is necessary, albeit in a nonspecific manner, and that the static magnetic component of a quasistatic electromagnetic cell and tissue modifier can potentiate the biological activity characteristic of the time-varying component.
Subsequent to these findings, Polk raised the possibility that the biological activity of low frequency time-varying magnetic fields may stem from an interaction with the static component of the earth's geomagnetic field, which is on the order of 0.3-0.5 gauss. Polk pointed out that important biological ions such as calcium could be placed into cyclotron resonance with the time-varying field according to the equation ##EQU1## where B is the field strength of the static magnetic component parallel to the time-varying field vector, q/m is the charge to the mass ratio for a particular ionic species, and f is the cyclotron resonance frequency. (Polk C., Bioelectromagnetics Soc., 6th Annual Meeting, p. 77, 1984; URSI XXI General Assembly Abstract, p. 25, 1984). A necessary condition for cyclotron resonance requires that a time-varying electric field be perpendicular to a static magnetic field. The condition is met by a static magnetic field and time-varying magnetic field with parallel components, since a time-varying field induces an electric field perpendicular to its own magnetic vector.
Blackman later reported that static magnetic fields on the order of the earth's geomagnetic field strength did indeed alter the frequency at which a time-varying field possessed biological activity. However, this was not due to a cyclotron resonance effect since the static field and time-varying field were at right angles to one another (Blackman, C. F., et al., Bioelectromagnetics, 6: 327-337, 1985).
Liboff pursued the idea of cyclotron resonance and has since published several papers expanding upon the theory and demonstrating its practical application. (Liboff, A. R., in Interactions Between Electromagnetic Fields and Cells, Chiabrera, A., et al eds, Plenum Press 1985; McLeod, B. R., and Liboff, A. R., Bioelectromagnetics 7: 177-189, 1986; Smith, S. D., et al, Bioelectromagnetics 8: 215-227, 1987).
Other models have theorized that the interaction between a low intensity time-varying magnetic field and static magnetic field can affect the motion of an ion near its membrane binding site through the magnetic component of the Lorentz force (Chiabrera, A., et al., in Interactions Between Electromagnetic Fields and Cells, Chiabrera, A., et al, eds, Plenum Press (1985). As a further development, Polk has attempted to explain the results of Blackman by postulating an ion precessional magnetic resonance mechanism, where resonant frequencies occur at one-half the cyclotron resonant frequency. (Polk, C. Abst., Trans. Bioelectric Repair and Growth Society, Pg. 23, 1987).
It is reasonable to assume that both cyclotron resonance and ion precessional magnetic resonance constitute conditions sufficient to produce biological activity, although it is quite clear that neither is strictly necessary. There are many reports of signals not near either resonance condition that possess biological activity. However, the resonance systems hint at a deep underlying mechanism associated with what is referred to as the "frequency window", since both modes exhibit biological activity at odd harmonics only. The reason for this is not understood at this time. So while progress has been made toward understanding the nature of the frequency window, the problem is far from resolved.
Much less understood and about which little attention has been focused, is the nature of the "amplitude window", which refers to the intensity of a biologically active electric or magnetic field. The amplitude of a time-varying magnetic field at which biological activity is conveyed appears to be windowed within low amplitude ranges near geomagnetic field strengths. Findings of this nature are useful in speculating about natural mechanisms that may have evolved between living systems and the earth's geomagnetic environment. For instance, Smith et al, (see reference above) using a cyclotron resonance system found a peak in the biological activity of the time-varying field at approximately 0.2 gauss.
Toward controlling the earth's geomagnetic field, these authors first cancelled the ambient field and then added precisely defined magnetic field strengths to the environment. Three pairs of coils in Helmholtz flux-aiding configuration were used. Two pairs of bucking coils were used to nullify the horizontal (x-axis) and vertical (y-axis) components of the earth's magnetic field density. The y-axis (east-west) was brought to zero by orienting the x-axis directly along the north-south axis of the earth's magnetic field. Thus, precise regulation of field strengths and orientations are necessary to produce resonance conditions in the geomagnetic range, since the earth's field is comparable in strength to the imposed conditions.
In fact, practically all of the experiments reported display an intense focus on low-level fields at or not far from geomagnetic conditions. This has limited the scope of clinical bioelectromagnetics because low-level fields deposit only miniscule amounts of biologically active energy into living systems and presents practical problems as discussed above. At present no methods have been reported to modulate the amplitude at which a time-varying magnetic field is biologically active. However, according to a novel aspect of the present invention a method for increasing or decreasing the intensity of the time-varying field while maintaining biological activity according to specific cellular mechanisms is given below. The distinct advantages of the method are illustrated with specific examples.
Due to certain inherent characteristics of a system, some systems demonstrate amplitude windows that appear relatively fixed, while other systems have amplitude windows that appear relatively not fixed.
Consider the situation where an important ion such as calcium is either electrogenically driven into the cell through specific channels or where fields trigger mechanisms that allow the ion to enter through voltage sensitive gating processes. The change in internal calcium can cause many effects, but if the concentration exceeds specific levels, the cell will react by actively pumping out calcium in order to maintain ionic homeostasis. Thus, a relatively high amplitude time-varying field that forces calcium into the cell may appear inactive since the cell counteracts the effect of the field. Likewise, an excessive induced voltage would not trigger a voltage sensitive gating mechanism, since an electric field beyond the ranges of the amplitude window would not be recognized as biological information. In these cases it is appropriate to consider the electrical amplitude window fixed. The innovation here is that the amplitude of the time-varying magnetic field can actually be decreased if the static magnetic field strength is increased. Although this phenomenon is not limited to resonant conditions, it is easier to explain and easier to understand if such an example is given.
According to the equations given above, an increase in the static magnetic field necessitates a proportional increase in the resonant frequency. This means that more electrical energy will be induced in a living system at a given magnetic amplitude since the electric field intensity is proportional to the rate of change of the magnetic field, E.alpha.dB/dt. So if the amount of calcium, for instance, that enters the cell is related to the field intensity through voltage sensitive gating processes, or through an induced calcium current wherein only limited amounts of calcium entry produce an observable effect, then it can be seen that the amplitude of the time-varying magnetic carrier must be decreased in order to maintain the electric field intensity within the appropriate range.
Similar arguments independent of resonance considerations can be made on the basis of the Lorentz force and the velocity imparted to an ion by the induced electric field. Basically, if the magnitude of the Lorentz force affects a critical cell function such as membrane mediated ion binding, then a higher static interacting with an ion at lower velocity still produces a Lorentz force in the appropriate range. The Lorentz force is given by F=qv.times.B, where q is the charge of the particular ion, v is its velocity and B is the static magnetic field amplitude. The magnitude of the force is given by the vector cross produce.
Exposing cells and tissues with relatively fixed amplitude windows to static magnetic field strengths, greater than geomagnetic field intensities, on the order of at least 3-5 gauss, for example, (although much greater intensities can be used) has significant implications in the design of clinical bioelectromagnetic devices. That is by supplying a relatively high static field from a permanently magnetized material or the like, the energy requirement of the device is reduced, since the magnetic amplitude of the time-varying field can be reduced. Thus, this is a method that facilitates the portability of clinical bioelectromagnetic devices.
This minimum threshold of 3-5 gauss is chosen to keep the variation in the resonance conditions due to the geomagnetic field to less than 10%. While it is preferred to have a tolerance of 10%, greater tolerances could be acceptable in certain circumstances.
Now consider the situation, where due to inherent characteristics of a system, the amplitude window is not fixed. In this situation, the amplitude window of cells and tissues increases with increasing static magnetic field strengths. That is increasing amounts of biologically active energy can be deposited into cells and tissues as the ambient static magnetic environment is increased. This is the method of bietic scaling. (The term bietic scaling also applies to situations where the amplitude window is fixed as described above.) Here, as in the former case, it is instructive to consider voltage sensitive gating processes at the direct effect of electric fields on specific ions. Resonance considerations are offered for simplicity as before.
The motion of an ion in resonance within a specific membrane channel must be confined to certain boundaries and gyroradi in order not to disturb the microenvironment of the channel. For instance, if an electric field were great enough to impart a velocity to the ion such that it challenged the boundaries of the channel, then that channel would cease to function. However, a strong static magnetic field will create a Lorentz force that will constrain the radial motion of an ion. Note that the Lorentz force changes the direction of a charged particle with velocity, v, but does not change the magnitude of the velocity. So at higher frequencies where dB/dt increases, the ion is at higher kinetic and potential energy states, but the path of its motion can be kept in check by the static magnetic field. Therefore, the ion can still pass through the channel, but now it does so at a much higher energy level, which would be otherwise unattainable without the increased field strength of the static environment. Resonance is not a critical factor where it is desired to add energy to a charged particle traversing an ion channel while magnetically constraining the gyropath of the ion to the functional boundaries of the channel.
Voltage sensitive gating processes, which regulate the opening and closing of ion channels, may themselves show a sensitivity to the ambient state magnetic environment. For instance, the endogenous currents of cells generate Hall voltages in the presence of magnetic fields. It is conceivable that these voltages regulate what is observed as a voltage sensitive gate. In this model, the cell possesses properties of a magnetometer. As the ambient magnetic field increases, the Hall voltage increases, thereby raising the voltage amplitude at which the gate becomes sensitive. As the static magnetic field increases in strength, the cell becomes concomittantly responsive to increases in the amplitude of the time-varying magnetic field. Thus, the amount of biologically active energy that can be imparted to cells and tissues as biological information, increases as the static magnetic field increases.
Increasing the intensity of biologically active fields has considerable advantages over state-of-the-art devices. As stated earlier, cells make a strong attempt at maintaining ionic homeostasis. There is no evidence that low intensity devices can overcome cellular homeostasis. That is, at low energy levels, biologically active fields merely act to trigger biological processes that are poised for activation. As such, low intensity devices cannot redirect physiologic processes. On the other hand, high-intensity devices can overcome homeostatic drive and redirect the function of cells and tissues.
Consider for example the transmission of a sensory stimulus across a synaptic junction. The transmission of an action potential is governed by the release of specific neurotransmitters. This release is in turn dependent upon controlled calcium uptake by the axonal membrane at the synapse.
Since calcium concentrations external to the cell are orders of magnitude greater than internal concentrations, membrane channels are either closed or largely concerned with pumping calcium out of the cell in order to maintain homeostasis. Weak biologically active systems can cause a transient and modest increase in internal calcium concentrations, but they are not intense enough either to keep the channels open for prolonged periods or to continually force calcium inward against homeostatic mechanisms. A high intensity biologically active system, on the other hand, can cause enough calcium to enter the cell such that the normal intake associated with neurotransmitter release is prevented by an unfavorable electrogenic gradient. This then leads to the disruption of a sensory signal and a loss of sensation in the area. Thus, an application of bietic scaling, the increasing of the biologically active amplitude window, is toward pain relief. High-intensity biologically active devices offer a means of true electroanesthesia.
Another application of bietic scaling is in the area of bioenergetics, the generation of high energy compounds by cells, Mitochondria produce the bulk of the high energy compound ATP, but only in the presence of oxygen. In the process of oxidative phosphorylation, ADP is converted to ATP by coupling to, or incorporating the energy that is released by a proton traversing the electric gradient of the mitochrondrial membrane. The amount of ATP made is directly related to the energy states of the proton. Adding a significant amount of energy to the proton, either potential or kinetic, increases the amount of ATP synthesized. Thus, the efficiency of cellular energy production is markedly enhanced by high-intensity resonant or non-resonant biologically active time-varying magnetic fields. This is an important consideration in biological systems that are compromised by inadequate oxygen levels.
In effect, through bietic scaling, electromagnetic fields are metabolized to ATP in a manner analogous to photosynthesis, a process termed bietic synthesis. This has many clinical applications in situations that would benefit from increased ATP synthesis, among which are: wound healing, nerve regeneration, compensation of vascular insufficiency, and traumatic ischemia. In the use of bietic scaling, the amplitude of the time-varying magnetic field can be adjusted automatically by the electronic means according to the amplitude of the static magnetic field and visa-versa. In the case where bietic scaling is applied to a fixed amplitude window, the amplitude of the time-varying field can be inversely proportional to the static magnetic field amplitude. For an amplitude window that is not fixed, the amplitude of the time-varying field increases proportionally to the static magnetic field amplitude. If the devices described are being used to generate resonant conditions, the frequency of the time-varying field is also adjusted automatically to the static field strength by means which can be accomplished by those with ordinary skill in the art, for instance, through calibration of the current driving the static magnetic field. Proportionally constants of amplitude to frequency can be preselected to met the conditions required for the chosen resonant ion. For autoresonance signals, the frequency of the signal is calibrated to the net direct current bias of the current that drives the time-varying field.
It is also been reported that applying electric fields to the ear produces neurotransmitter effects that relieve anxiety and addictive behaviors such as drug use and smoking. However, there are definite advantages of using magnetic fields to produce localized electric fields as the foregoing has shown.